The hepatitis C virus (HCV) is the leading cause of chronic hepatitis, which can progress to liver fibrosis leading to cirrhosis, end stage liver disease, and HCC (hepatocellular carcinoma), making it the leading cause of liver transplantations. Anti-HCV therapy, based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin, suffers from limited efficacy, significant side effects, and is poorly tolerated in many patients. This prompted the search for more effective, convenient and better-tolerated therapy. Recently, certain protease inhibitors have been approved for use in combination with peginterferon plus ribavirin. However, there is a need for improved protease inhibitors.
WO-2007/014926 describes macrocyclic cyclopentane and proline derivatives including the compound TMC-435 with the structure represented hereafter.

TMC-435 is a very effective inhibitor of the HCV NS3 protease and is particularly attractive in terms of pharmacokinetics. Due to its favorable properties it is being developed as an anti-HCV drug. Consequently there is a need for producing larger quantities of this active ingredient based on processes that provide the product in high yield and with a high degree of purity.
Synthesis procedures to prepare TMC-435 have been disclosed in WO-2007/014926 wherein TMC-435 is identified as compound (47) in Example 5 on page 76.
An important step in the synthesis of TMC-435 as described in WO-2007/014926 is the ring-closing metathesis (RCM) which is depicted below:
Said ring-closing metathesis has been described in WO-2007/014926 in Example 4 Step E on page 74. Ring-closing metathesis of intermediate (44) in WO-2007/014926 is done by means of a Hoveyda-Grubbs first-generation catalyst in 1,2-dichloroethane at 75° C. for 12 hours resulting in intermediate (45) with a 60% yield. Large amounts of oligomeric byproducts are formed under these conditions, and tedious purification procedures, e.g. preparative chromatography, are required to isolate the product from the reaction mixture.
The efficiency by which the ring-closing metathesis cyclization occurs is important because the starting material, i.e. compound (1) or intermediate (44) in WO-2007/014926, is the result of a long multi-step process. The ring-closing metathesis reaction produces side products such as dimers and polymers thereby lowering the yield and complicating product isolation. One solution that has been proposed in Goldring et al., Tetrahedron Letters 39, 4955-4958 (1998), is the introduction of a N-protective group, in particular a Boc group, on the secondary amide function which is removed after the ring-closing metathesis. Said introduction and removal of a N-protective group to increase the yield of ring-closing metathesis in the synthesis of macrocyclic compounds has also been described in WO-2007/030656, WO-2009/073780 and WO-2010/015545. The N-protective group described in said references is e.g. C1-6alkyloxycarbonyl such as Boc (tert-butyloxycarbonyl), C1-6alkylcarbonyl, benzoyl and arylcarbonyl (in particular, the N-protective group is benzoyl).
When applying this N-protective group technology using Boc in the ring-closing metathesis of compound (1) it turned out that the Boc-group could only be removed from the macrocyclic metathesis product under drastic conditions, in particular prolongued heating with strong acids (e.g. sulfuric acid or benzenesulfonic acid), resulting in product decomposition during the Boc-deprotection process. This procedure is depicted below in Scheme 1.
wherein Q=

When applying the N-benzoyl protective group, on the other hand, cleavage of the benzoyl protecting group can be done by treatment of the N-benzoylated macrocycle with bases such as KOH. This cleavage is also accompanied by product loss due to non-selective attack of the base and ring opening of the macrocyle. Introduction of both the Boc and the benzoyl group needs an additional synthesis step, and a purification is necessary before the ring closing metathesis to avoid catalyst poisoning.
Hence there is a need to improve the efficiency of this ring closing metathesis reaction, preferably with as few additional steps as possible. In particular there is a need for a protecting group on the secondary amide function that can be removed easily under non-drastic reaction conditions.
It now has been found that halogenated acyl groups can be used in situ in the ring-closing metathesis reaction and can be removed easily upon completion of the reaction. It further has been found that the protection-macrocyclization-deprotection cycle can be conducted in a one-pot process in high yield of the end product, which is obtained in high purity.
The process of the invention offers a straightforward, quick and economic procedure to produce compound (2), which can easily converted to the end product TMC-435.